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Yoshihiro Fukumoto,1,2 Tome Ikezoe,2 Masashi Taniguchi,2 Yosuke Yamada,3 Shinichiro Sawano,4 Seigo Minani,5 Tsuyoshi Asai,6 Misaka Kimura,7,8 Noriaki Ichihashi2 1Department of Physical Medicine and Rehabilitation, Kansai Medical University, Hirakata, Japan; 2Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 3National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan; 4Rehabilitation Units, Shiga University of Medical Science Hospital, Otsu, Japan; 5Faculty of Rehabilitation, Osaka Kawasaki Rehabilitation University, Kaizuka, Japan; 6Faculty of Rehabilitation, Kobe Gakuin University, Kobe, Japan; 7Institute for Active Health, Kyoto University of Advanced Science, Kameoka, Japan; 8Graduate School of Nursing, Doshisha Women’s College of Liberal Arts, Kyotanabe, JapanCorrespondence: Yoshihiro FukumotoDepartment of Physical Medicine and Rehabilitation, Kansai Medical University, 2-5-1 Shin-Machi, Hirakata City, Osaka, Osaka, JapanTel +81-72-856-2307Fax +81-72-856-2150Email fukumoty@hirakata.kmu.ac.jpPurpose: Ultrasound-based prediction methods for the detection of low muscle mass for sarcopenia in older adults have been explored previously; however, the muscle that most accurately predicts it is unclear. This study aimed to clarify prediction accuracy and cut-off values for ultrasound-derived thigh and lower leg muscle thickness (MT) to detect low skeletal muscle mass index (SMI) in older adults and to estimate cut-off values based on two standard deviations (SD) below younger adult means for the corresponding muscles as an early detection tool for site-specific low muscle mass.Methods: This study included 204 community-dwelling older (64 males, 140 females, mean age: 75.4 years) and 59 younger (31 males, 28 females, mean age: 22.3 years) adults. The MT of the rectus femoris, vastus intermedius, gastrocnemius, and soleus muscles was measured using ultrasound; SMI was measured using bioelectrical impedance analysis.Results: The prevalence of a low SMI among older adults was 20.3% (n=13) for males and 21.4% (n=30) for females. The receiver operating characteristic analysis revealed that the total MT for the four muscles measured presented the highest area under the curve (AUC) value to predict low SMI for males (0.849) and females (0.776). The AUC value was the highest for the total MT of the gastrocnemius and soleus muscles for males and the gastrocnemius for females (0.836, 0.748; cut-off value: 5.67 cm, 1.42 cm, respectively). Muscle-specific differences between the low SMI-predicting and SD-based cut-off values were observed. The SD-based value for the rectus femoris (1.85 cm) was substantially higher than the low SMI-predicting value (1.51 cm) in males.Conclusion: Ultrasound measurement of lower leg muscles may be a simple, robust measure to detect low muscle mass for sarcopenia. Additionally, cut-off values for site-specific muscle mass loss may not always agree with those for whole-limb muscle mass loss.Keywords: area under the curve, bioelectric impedance, skeletal muscle, ultrasound

Momoko Yamagata,1 Tome Ikezoe,1 Midori Kamiya,1 Mitsuhiro Masaki,2,3 Noriaki Ichihashi1 1Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, 2Department of Physical Therapy, 3Institute for Human Movement and Medical Sciences, Niigata University of Health and Welfare, Niigata, Japan Purpose: Sample entropy (SampEn) is an analysis to evaluate movement complexity of the center of pressure (COP). A lower value of SampEn indicates lower complexity of COP variability, that is, rigidity, and lower degrees of freedom. Previous studies reported the association of increased SampEn with improved standing balance ability in young subjects. However, no studies have examined these relationships among older adults. Thus, we aimed to investigate the relationship between SampEn and standing balance ability in older adults.Subjects and methods: The subjects were 33 institutionalized older adults (aged 82.2±6.5 years). COP during static standing was measured. The standard deviation (SD) values of COP and SampEn in the sagittal and frontal planes were calculated using time series data. One-leg standing test (OLST), functional reach (FR) test, and lateral reach (LR) test were also measured to evaluate standing balance ability.Results: OLST, FR, and LR were 6.5±8.3 s, 19.8±5.9 cm, and 18.2±6.4 cm, respectively. Pearson correlation analysis revealed that SampEn in the sagittal plane significantly correlated with OLST (r=-0.35) and FR (r=-0.36). However, SampEn in the frontal plane and SD of COP in both sagittal and frontal planes had no relationship with any of the clinical balance tests.Conclusion: Lower SampEn implies rigidity for postural control. In the present study, it was found that lower SampEn in the sagittal plane was related to a higher balance function, which suggests that older adults utilized body rigidity to maintain postural stability as a compensative strategy. Keywords: older adults, posture, balance, standing, complexity, entropy

Shosaku Nomura,1 Yoshinobu Maeda,2 Kazuyoshi Ishii,1 Yuta Katayama,3 Hideo Yagi,4 Naoto Fujishima,5 Shuichi Ota,6 Masato Moriyama,7 Takayuki Ikezoe,8 Yasuhiko Miyazaki,9 Kunio Hayashi,10 Shinya Fujita,1 Atsushi Satake,1 Tomoki Ito,1 Taiichi Kyo,3 Mitsune Tanimoto2 1First Department of Internal Medicine, Kansai Medical University, Hirakata, 2Department of Hematology and Oncology, Okayama University, Okayama, 3Division of Hematology, Hiroshima Red Cross Hospital, Hiroshima, 4Division of Hematology, Kidai Nara Hospital, Ikoma, 5Department of Hematology, Naphrology, and Rheumatology, Akita University, Akita City, 6Division of Hematology, Sapporo Hokuyu Hospital, Sapporo, 7Department of Hematology, Niigata University, Niigata, 8Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, 9Division of Hematology, Oita Hospital, Oita, 10Division of Hematology, Meiwa Hospital, Nishinomiya, Japan Background: Conditioning regimens including total body irradiation (TBI) or cyclophosphamide can mobilize high-mobility group box 1 (HMGB1) to peripheral blood. Additionally, increased plasminogen activator inhibitor (PAI)-1 levels are associated with post-allogeneic hematopoietic stem cell transplantation (aHSCT). However, changes to circulating levels of HMGB1 after aHSCT are poorly understood. Materials and methods: The study cohort included 289 patients who underwent aHSCT at one of 25 institutions in Japan. We have investigated the relationship between HMGB1 and PAI-1 following aHSCT. A significant increase in HMGB1 levels occurred after conditioning treatment. Additionally, levels of HMGB1 at day 0 were significantly increased in TBI+ patients and cyclophosphamide/TBI patients. Conclusion: Our data revealed that an increased level of HMGB1 at day 0 following aHSCT correlates with increased PAI-1 after aHSCT, which is consistent with previous reports. Increased HMGB1 at day 0 after a conditioning regimen may play a role in transplantation-associated coagulopathy following aHSCT, because PAI-1 can accelerate procoagulant activity. Keywords: PAI-1, transplantation-associated coagulopathy, aHSCT, TBI, HMGB1

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Survival of cancer cells relies on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The IRE1α-XBP1 pathway, a key branch of the UPR, is activated in many cancers

HIV-1 protease inhibitor (PI), nelfinavir (NFV) induced growth arrest and apoptosis of NCI-H460 and -H520, A549, EBC-1 and ABC-1 non-small-cell lung cancer (NSCLC) cells in association with upregulation of p21waf1, p27kip1 and p53, and downregulation of Bcl-2 and matrix metalloproteinase (MMP)-2 proteins. We found that NFV blocked Akt signalling in these cells as measured by Akt kinase assay with glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) as a substrate. To explore the role of Akt signalling in NFV-mediated growth inhibition of NSCLC cells, we blocked this signal pathway by transfection of Akt small interfering RNA (siRNA) in these cells; transient transfection of Akt siRNA in NCI-H460 cells decreased the level of Bcl-2 protein and slowed their proliferation compared to the nonspecific siRNA-transfected cells. Conversely, forced-expression of Akt partially reversed NFV-mediated growth inhibition of these cells, suggesting that Akt may be a molecular target of NFV in NSCLC cells. Also, we found that inhibition of Akt signalling by NFV enhanced the ability of docetaxel to inhibit the growth of NCI-H460 and -H520 cells, as measured by MTT assay. Importantly, NFV slowed the proliferation and induced apoptosis of NCI-H460 cells present as tumour xenografts in nude mice without adverse systemic effects. Taken together, this family of compounds might be useful for the treatment of individuals with NSCLC.

12-0-tetradecanoylphorbol-13-acetate (TPA) stimulates protein kinase C (PKC) which mediates apoptosis in androgen-sensitive LNCaP human prostate cancer cells. The downstream signals of PKC that mediate TPA-induced apoptosis in LNCaP cells are unclear. In this study, we found that TPA activates the c-Jun NH2-terminal kinase (JNK)/c-Jun/AP-1 pathway. To explore the possible role that the JNK/c-Jun/AP-1 signal pathway has on TPA-induced apoptosis in LNCaP cells, we stably transfected the scaffold protein, JNK interacting protein 1 (JIP-1), which binds to JNK inhibiting its ability to phosphorylate c-Jun. TPA (10(-9)-10(-7) mol l(-1)) caused phosphorylation of JNK in both wild-type and JIP-1-transfected (LNCaP-JIP-1) cells. It resulted in phosphorylation and upregulation of expression of c-Jun protein in the wild-type LNCaP cells, but not in the JIP-1-transfected LNCaP cells. In addition, upregulation of AP-1 reporter activity by TPA (10(-9) mol l(-1)) occurred in LNCaP cells but was abrogated in LNCaP-JIP-1 cells. Thus, TPA stimulated c-Jun through JNK, and JIP-1 effectively blocked JNK. TPA (10(-12)-10(-8) mol l(-1)) treatment of LNCaP cells caused their growth inhibition, cell cycle arrest, upregulation of p53 and p21waf1, and induction of apoptosis. All of these effects were significantly attenuated when LNCaP-JIP-1 cells were similarly treated with TPA. A previous study showed that c-Jun/AP-1 blocked androgen receptor (AR) signaling by inhibiting AR binding to AR response elements (AREs) of target genes including prostate-specific antigen (PSA). Therefore, we hypothesised that TPA would not be able to disrupt the AR signal pathway in LNCaP-JIP-1 cells. Contrary to expectation, TPA (10(-9)-10(-8) mol l(-1)) inhibited DHT-induced AREs reporter activity and decreased levels of PSA in the LNCaP-JIP-1 cells. Taken together, TPA, probably by stimulation of PKC, phosphorylates JNK, which phosphorylates and increases expression of c-Jun leading to AP-1 activity. Growth control of prostate cancer cells can be mediated through the JNK/c-Jun pathway, but androgen responsiveness of these cells can be independent of this pathway, suggesting that androgen independence in progressive prostate cancer may not occur through activation of this pathway.

The aims of this study were to analyze the clinical features of a large number of cases with disseminated intravascular coagulation (DIC) associated with acute leukemia and to assess the safety and efficacy of thrombomodulin alfa (TM-α) using the French-American-British (FAB) classification of hematological malignancies. We retrospectively examined 644 patients with acute leukemia in postmarketing surveillance for TM-α. M3, M2, M4, M1, and M5 subtypes of acute myeloid leukemia (AML) and L2 and L1 subtypes of acute lymphoblastic leukemia (ALL) have been found more frequently among patients with DIC. Bleeding symptoms at baseline were more frequent in M3 and M7 subtypes. Fibrinogen concentrations were lower, and plasmin-plasmin inhibitor complex values were higher in M3 and Philadelphia-positive (Ph+) ALL. Overall DIC resolution rate was 60.2%, higher in L1 and Ph+ ALL, lower in M1, and generally higher in ALL than in AML. Overall survival rate was generally high, at 79.8%, with higher rates in L3, Ph+ ALL, and M3. Regardless of FAB subgroup, TM-α showed improved bleeding symptoms and DIC scores in clinical practice for DIC patients with acute leukemia.